Framework for Multistakeholder Patient Registries in the Field of Rare Diseases

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.


Introduction
Rare neurogenetic diseases (RNDs) consist of a diverse group of diseases profoundly affecting motor and cognitive function and life expectancy. 1 While treatments remain limited, advances in genetic diagnosis and orphan drug development and legislations are encouraging.In fact, orphan drugs for RND and inborn errors of metabolism dominate nononcological orphan drugs in both the United States [2][3][4] and the European Union. 5ew therapies such as gene therapy are promising but also pose new academic, regulatory, and financial challenges.These challenges include lack of evidence on (long-term) safety, effectiveness, and appropriate use at the time of market entry and concerns regarding cost-effectiveness and budget impact.
Patient registries are considered to be crucial for development and regulation of orphan drugs for the treatment of RND. 6 Unlike natural history studies that gather detailed data from untreated patients in controlled settings, registries are systems designed to broadly collect, store, and use real-world data.8][9] Registries can also inform regulatory decisions and filling evidence gaps after clinical trials such as uncertainties about long-term safety, optimal use in the realworld setting, and (cost-)effectiveness. 6,[10][11][12][13] Besides that, prices for orphan drugs are generally high and exceed cost-effectiveness thresholds. 14,15Therefore, national organizations responsible for reimbursement and pricing struggle with decision making leading to delayed or hampered access. 16Registries can monitor outcomes and cost-effectiveness in the real world after approval and reimbursement decisions, so-called postauthorization evaluation. 10,15This may be accompanied by conditional reimbursement schemes and outcome-based managed entry arrangements, 17 for which a registry can provide the infrastructure. 18When multiple treatment options are available, registries can be used for standardized comparison to enable appropriate use, facilitating a lifecycle approach to drug regulation. 19,20It is important to note that knowledge gained through registries may help patients and families in shared decision making and guide expectations in treatment counseling.
Efficient patient registries that serve the purposes described above are crucial to optimize the care of RND.The exact roles of such registries are, however, not yet fully defined, and their implementation is still pioneering work for which practical guidance is lacking.In this study, we provide a practical framework to support the creation and implementation of patient registries, focusing on RND, to guide registry holders.The framework addresses common challenges and elaborates on possible approaches for building a data infrastructure with maximum impact on patient care by serving research, drug development, and regulatory and reimbursement decision making.

Framework Development Process
A group of researchers (D.H.S., C.E.M.H., N.I.W., S.B.) from the MLD initiative 21 and policy makers (H.P., K.K., L.T., V.V., W.G.) from the Dutch Health Care Institute (health technology assessment [HTA] body), all collaborating in the program "Managing Patient Registries for Expensive Drugs (RORDGM)," initiated this framework.A previous method for a framework about innovating HTA 22 was adapted to develop this framework.We worked in 3 stages: (1) qualitative systematic literature review to create the draft framework, (2) purposive sampling of 5 established international RND registries using a survey and interviews to collect experiences from registry holders, and (3) expert consultation using multistakeholder focus groups (patient representatives and articles about registries (eAppendix 1 and eFigure 1).The literature was qualitatively analyzed and abstracted using a combined multistep manual deductive and inductive coding approach.In the first step based on the domains used in the program RORDGM (deductive), information on "purpose and data," "IT infrastructure," "governance," and/or "financing" was extracted and ordered.Within these domains, inductive coding in step 2 (ordering, ranking, clustering), step 3 (abstraction, theming, heading), and step 4 (further abstraction, summarizing) led to the draft version of the conceptual framework.The interviews with existing registry holders (stage 2) helped in assessing whether all relevant aspects were addressed and to add practical tips.By using the draft framework as the starting point in stage 3, we were able to structure the discussion with the experts.A detailed description of the steps can be found in eAppendix 2. The framework incorporates standards, that is, best practices, for registry governance, financing, data, and IT infrastructure, categorized into 3 levels: (A) consistent findings from literature, interviews, and focus groups; (B) limited findings from literature, interviews, and focus groups but supplemented and endorsed by the authors; and (C) subject of discussion with inconsistent findings from literature, interviews, or focus groups.The framework also includes tips and tools that may be helpful to fulfil the suggested standards.

Data Availability
Data not provided in the article because of space limitations, including the list of prioritized topics in the focus groups and the list of participants, may, after approval of those involved, be shared at the request of any qualified investigator for purposes of replicating procedures and results.

Sample Registries
The sample registries, that is, Enroll-HD (Huntington disease), 23 International Niemann-Pick Disease Registry (INPDR), 24 4H registry (4H leukodystrophy), 25 SCA registry (spinocerebellar ataxias), 26 and VWM registry (Vanishing White Matter), 27 show differences in IT sophistication, data quality, number of employees, and financing models (eTable 1 under eAppendix 3).What they have in common is that emerging treatments are a significant driver of the registries and that the registry purposes are changing over time.
Overall, the interviews highlight the challenges and importance of creating and maintaining rare disease registries, including the need for adequate resources, staff, and IT systems, as well as navigating regulatory standards and involving patients and other stakeholders in the process.Enroll-HD stands out as a highly professional, European Medicines Agency (EMA)-qualified registry.Both Enroll-HD and INPDR praise the clarity and benefits of EMA qualification.INPDR transitioned from physician/researcher-led to community-led, with a trustee board encompassing patient representatives, clinicians, and researchers.The patient-initiated 4H registry outsourced organizational and IT aspects to the Rare-X platform to enable continuation.The academia-driven SCA and VWM registries yielded substantial academic output and accessibility to industry stakeholders, with the SCA registry partly reliant on industry funding.

Proposed Framework
The complete framework with the strengths of all recommendations and standards is presented in eTable 2 (under eAppendix 4), with Figure 2 showing a concise visual summary.Key findings and main characteristics are presented in the following.

Interests and Purposes
A Rare Disease Registry Should Be Multipurpose and Serve Different Stakeholders Stakeholders, including patients, physicians, researchers, regulators, payers, and pharmaceutical industry, have diverse interests in rare disease registries (eTable 3).All stakeholders benefit from high-quality data.Consideration of all interests in registry setup without prioritizing one interest over another is important.The different interests lead to various purposes of rare disease registries including research, care, regulatory, and reimbursement decision making (Table 1).While clear purposes are essential, flexibility and adaptability in registry design are also necessary to accommodate unforeseen future questions.Multipurpose registries are favored over single-purpose ones for rare diseases to avoid scattering, maximizing reuse of scarce rare disease data.

Governance A Transparent Governance Model Should Facilitate Collaboration and (Re)use of Data
A transparent governance model, that allows for some degree of flexibility and is suitable for data utilization, is needed (eTable 2, "Governance > Key governance principles").Timely data access by various stakeholders should be embedded in the governance model and publicly described to facilitate requests for access by third parties.

Broad Registry Ownership to Facilitate Data Use by Third Parties and Ensure Sustainability
There is no consensus on the preferred initiator and owner of registries (eTable 2, "Governance > Owner/initiator").However, there is consensus that in case of multipurpose registries, broad ownership, for example, multiple academic centers united in an international collaborative network or consortium, with engagement of different stakeholders is recommended.Various stakeholders, such as health authorities, patients, physicians, and pharmaceutical sponsors, are all considered to be suitable registry owners, either individually or in different combinations.A physician-led governance with substantial patient input can be a good option.There is general agreement that registries should not be owned by a single marketing authorization applicant/holder.Industry-led registries are noted for data quality control and sufficient funding, but conflicts of interest are identified as a downside.Furthermore, pharmaceutical industry might have concerns about data sharing with other companies or stakeholders.Academia-led registries are viewed favorably for their longer term focus and fewer commercial conflicts of interest.Pharmaceutical industry may also prefer registries driven by academic needs, enabling them to align their strategies with the latest research insights.Nonetheless, concerns are expressed about the time-consuming nature of registry management and potential issues regarding sustainable funding and guaranteeing timely data access.

Engaging Relevant Stakeholders in Early Registry Development
Collaborative efforts among diverse stakeholders are crucial for a registry's sustained success and impact (eTable 2, "Governance > Stakeholder role and engagement").Patient advocacy involvement in registry governance is important.These collaborations can be formalized in consortium agreements, in which a specific role for industry, without industry ownership, can be defined.Effective registry implementation requires managing interactions with regulatory authorities and ensuring clear communication among diverse stakeholders.
The Registry Management Team Should Include Clinical, Data Management, and Supportive Experts A proficient and diverse registry management team is essential for day-to-day registry operations, encompassing data processing, quality assurance, and fulfilling of various registry requirements (eTable 2, "Governance > Registry management team").The team typically includes disease expert clinicians, data stewards, a project leader, and secretarial support.A robust data management strategy with established standard operating procedures is vital.Specialized training for personnel and clear communication channels with a central contact point are necessary.

Dynamic Informed Consent for Data Reuse and Negotiating Legal Contracts Take Time
A dynamic and publicly accessible informed consent is deemed essential for data reuse and sharing (eTable 2, "Governance > Ethics, privacy safeguarding and law").Designing and negotiating consortium agreements and contracts can cause delay in setting up a registry but are essential to regulate collaboration and data reuse by different parties.

Financing
Funding From Multiple Sources to Maintain Independence and Ensure Sustainability Establishing a sustainable funding model involving different national and international funding sources is critical to ensure long-term sustainability and success in registry endeavors.Potential funders include public institutions, regulatory and reimbursement agencies, academia, and pharmaceutical companies, either individually or in combinations.Conditions for industry funding to maintain independence, integrity, and equitable data access for all stakeholders are added to the framework (eTable 2, "Financing > Sources of funding").

Fees for Data Can Be an Option
Free data sharing is sometimes advocated to endorse therapy development while charging fees may support financial sustainability.Fee structure should take into account the type of requester (e.g., academic vs industry) and the efforts necessary for data delivery.Multipurpose patient registries should involve multiple stakeholders in determining which data are to be collected in the registry (eTable 2, "Data > Procedure to establish data elements").An international consensus procedure might be an efficient method.Registry contents have different layers, ranging from the meaning of data to the technical coding of data.All these layers should be considered and tailored input from different stakeholders sought, as schematically presented in Figure 3.
Distinguish Core and Optional Data Items and Adhere to International Standards Differentiating core and optional data items is recommended.Implementing standardized core elements in adherence to international standards and ontologies across multiple registries is recommended.Examples are provided in the framework (eTable 2, "Data > Specific data elements").

Use Standardized Tools and Scoring Systems to Collect Neurologic Characteristics
Table 2 presents suggestions for collecting standardized and concise information on important commonalities of RND (Table 2).

IT Infrastructure
The IT Infrastructure Should Be Tailored to Registry Purposes and Facilitate Data Management and Data Use A registry's IT infrastructure is fundamental and supports data management, quality, reuse, analysis, privacy, security, and sustainability.Involving IT experts and data stewards in database design, even with existing software solutions, is important.Flexibility of the system and adherence to findable, accessible, interoperable, and reusable (FAIR) data principles Besides capturing or collecting data, the IT infrastructure should facilitate data use.Data sharing or access can be arranged in multiple ways as listed in the framework (eTable 2, "IT infrastructure > Data access").More advanced registry systems can function as a data analysis framework in which data can be queried instead of just captured.

FAIR Data Principles to Maximize Impact and Data Quality
The incorporation of FAIR data principles aids in augmenting data impact and quality.Key terms in the context of FAIR are explained in eAppendix 5, and an example of an ontological data model is presented in eFigure 2. Interoperability and alignment with other registries enable combining different data sources.Although a federated data model is considered

Psychiatric and behavioral problems
Presence of these problems as binary variable VABSs can be used to assess adaptive behavior (remotely)

Ataxia
Use of clinical scores can be considered, such as SARA, ICARS, and BARS

Spasticity
Presence of these problems as binary variable

Extrapyramidal movement disorders
Videos of movement disorders should be considered, but additional challenges for privacy and mode of storage should be taken into account

Peripheral neuropathy
Presence of these problems as binary variable

Epilepsy
Presence of these problems as binary variable beneficial, its current feasibility for a small registry is questioned.Clear perspectives on the required level of FAIR compliance for RND registries are still lacking.Moreover, there are challenges associated with implementing FAIR principles, such as limited availability of FAIR experts and labor-intensive implementation.

Further Considerations and Discussion
Framework for Rare Disease Registries In summary, patient registries for RND may serve different purposes for patients, physicians, researchers, regulators, HTA agencies, payers, and pharmaceutical industry.Despite diverse expectations, aligning registry requirements to accommodate all stakeholders is possible and preferred over multiple registry silos for a single rare disease.This study established standards for rare disease registries through a literature review and qualitative multistakeholder analysis.This framework guides registry holders in optimizing data utilization to accelerate therapeutic access and improve care in rare diseases.The framework addresses purposes for data utilization, governance, financing, data, and IT infrastructure.Key principles include that data should be quickly accessible, independent, and trustworthy.The governance should involve multiple stakeholders, including patient advocates.Data should be highly descriptive, machine-readable, and accessible through a shared infrastructure.Sustainable and independent financing of registries remains difficult.

Balancing Objectives and Flexibility
The need to define clear objectives at initiation of a registry and at the same time retain flexibility to adapt to future needs is challenging.Clear objectives help to keep focus in a research plan, to limit the number of data elements and associated workload, and to acquire funding for a well-defined project.A possible solution to maintain the registry's flexibility and sustainability lies in its governance model and IT infrastructure.Engaging different stakeholders while maintaining independency anticipates future needs.Independence without commercial interests will ensure that different companies and governmental bodies can trust data from the registry and leverage compliance to commitments such as regulatory postauthorization surveillance. 28Legally binding contracts can prevent data loss if ownership changes.An IT infrastructure adhering to FAIR principles facilitates reuse, which again benefits the flexibility of the registry.Striking a balance between clear objectives at the start of the registry and retaining flexibility is essential for accommodating evolving needs in the field.
Challenges in Real-World Data Acceptance and Quality Assessment Patient registries collecting real-world data, though valued, 29,30 face hesitancy in their use.Multiple clinicians, for example, emphasized in the focus groups that natural history studies may offer more rigor and detail but they require more resources and impose higher patient burden and potential biases, for example, regarding participating patients.Multiple stakeholders raised their concerns that payers, regulators, and even journals may be reluctant to trust real-world data, often citing doubts about data quality.Despite evidence showing their noninferiority to more controlled sources such as postapproval trials, 31 transparent quality standards for registries are lacking.3][34][35] Currently, the EMA assesses the usability and quality of a registry case-by-case, for example, in a qualification or scientific advice procedure.HTA bodies in Europe and Canada have used EUnetHTA's ReQUEST tool, which aids in creating a comprehensive overview of a registry. 34The precise implementation, for example, when regulatory/HTA bodies should complete the tool or when an auto-assessment is helpful, still needs to be defined.In the focus groups, it was also suggested that the European Reference Networks might be involved in rare disease registry assessment in Europe, similar to their auditing activities for expert centers.Specific quality standards or a quality mark, feasible also for small (ultra)rare disease registries, may be helpful.

International Data for Local Questions
Another complicating factor for use of registries by decision makers noted in the focus groups was that cross-country and even intracountry differences in treatment access and use hamper comparative assessments.In addition, national regulatory evaluations and HTA may lead to local questions for which authorities typically prefer local registries.In rare diseases, adequate powering of these local studies is challenging and often impossible.National regulatory/HTA questions should preferably be accommodated using international registries.The rationale for this becomes even stronger with the EU HTA Regulation being launched in 2025 and enabling joint assessments of advanced therapy medicinal products in Europe.Based on our findings, we suggest that authorities should be open to use international registry data for local questions, which will lead to better and quicker answers than relying only on a small national data pool.

Perspectives on PROMs
Health-related quality-of-life assessments using PROMs are generally recommended to collect in registries.However, opinions on relevance and purposes vary widely.The focus groups clarified that PROMs are useful in the context of health economic evaluation.For health economics, it was deemed desirable to use the same tool across multiple diseases.On the contrary, disease-tailored PROMs were deemed to be more clinically relevant.Further research is needed on the meaning and the correct application of PROMs in different diseases.
The current work of EMA on PROMs and patient experience data in regulatory context is a notable effort. 36ward Machine-Readable Data The FAIR data movement promotes machine-readable federated data models. 37In practice, this is not always feasible for small registries for (ultra)rare disorders. 20There is a gap between technical experts and regulatory/HTA representatives clearly advocating FAIR principles and registry holders, as illustrated in the focus groups where FAIR principles and IT infrastructure were among the least prioritized topics in the focus groups.Practical guidance and registry-specific advice on FAIR principles, especially in lay language, are lacking.Policy makers emphasize the urgency of applying FAIR principles in health data as illustrated by the DARWIN-EU program 38 and the European Health Data Space.Initiatives such as the personal health train or other federated data analytics systems are promising to overcome scattered health data sets. 39,40In rare diseases, there are additional challenges that should be taken into account.For example, the significant amount of unstructured (source) data, resulting from unique disease characteristics and highly specific measurements, is problematic.In addition, for some (ultra)rare diseases, the total number of patients worldwide is so small that a central database is feasible (and maybe preferable) and making various databases machine-actionable not worth the effort. However [n = 4], clinicians [n = 6], HTA experts and regulators and payers [n = 7], industry representatives [n = 7], and data/information technology [IT] specialists [n = 5]) to refine the framework (Figure 1).The framework was drafted based on literature (stage 1) to make a comprehensive but manageable overview of the available guidance documents Glossary EMA = European Medicines Agency; HD = Huntington disease; HTA = health technology assessment; INPDR = International Niemann-Pick Disease Registry; IT = information technology; PROM = patient-reported outcome measure; RND = rare neurogenetic disease; RORDGM = Managing Patient Registries for Expensive Drugs; SCA = spinocerebellar ataxias; VWM = Vanishing White Matter.

Figure 2
Figure 2 Schematic Summary of the Framework for Rare Disease Registries

Research•
Prevalence and geographical distribution • Natural history • Genotype-phenotype correlations • Trial execution and design • Addition to trial data • Alternative for placebo (in case this is not ethical) • More effective research and trials • To better reflect the needs of patients in the design of clinical trials • Supporting the setup of (registry-based) studies • Identifying and developing biomarkers • Developing outcome measures • Drug development • Improving effectiveness • Appropriate use of drugs Care • Supporting health and social service in rare diseases • Development of disease prevention activities • Newborn screening programs • Multiple treatments for a single disease can be compared • Clinical guideline development • Shared decision making • Clinical decision making • Appropriate use of drug Regulatory decision making on safety, effectiveness, implementation, and appropriate use • To gain market approval and access • Maintaining a marketing authorization • Long-term monitoring of innovative treatments • Monitoring effectiveness (periodic reporting of clinical outcomes on individual and aggregated level) • Pharmacovigilance (expedited and periodic reporting of individual and aggregated adverse events) • Post-marketing surveillance • Safety monitoring Reimbursement decision making • Effectiveness of treatment • Providing data for HTA parameters and the appropriate use of drugs • Comparing treatments and diagnostics • Identifying subpopulation for treatment • Mitigating uncertainty in lack of evidence and expensive drugs

DataA
Consensus Procedure Involving Multiple Stakeholders to Establish Selection of Data Items Patient-Reported Outcome Measures Are Valuable and Required for HTA Patient-reported outcome measures (PROMs) should be disease-specific, culturally adapted, validated, and electronically captured.Especially HTA agencies have considerable interest in PROMs on quality of life, although there is no consensus on the specific tool to be used.Integration of PROMs into standard care during hospital visits helps prospective collection of such data to inform future costeffectiveness and regulatory questions.Robust data quality procedures are vital throughout the data lifecycle, including entry, monitoring, and use stages.Strategies included minimizing missing and erroneous data during entry through software tools, varied data sources, and validation.The procedure to obtain an EMA qualification improves data quality.Data quality measures should be tailored to registry objectives to avoid excessive workloads.Frequent updates, longitudinal data, timely data entry after patient visits, and diagnosis checks can enhance data quality.Patient involvement is possible to add missing and update personal data, although concerns exist about the heightened monitoring demands required for patient-entered data because of quality requirements for research data and patients' health literacy.

Figure 3
Figure 3 Schematic Visualization of the Gradient of Stakeholders' Influence on Collected Data Abbreviations: BARS = Brief Ataxia Rating Scale; CFCS = Communication Function Classification System; EDACS = Eating and Drinking Ability Classification System; ELFC-MLD = Expressive Language Function Classification in Metachromatic Leukodystrophy; GMFC-MLD = Gross Motor Function Classification in Metachromatic Leukodystrophy; GMFCS = Gross Motor Function Classification System; HGVS = Human Genome Variation Society; HUI = Health Utilities Index; ICARS = International Cooperative Ataxia Rating Scale; Katz ADL = Katz Index of Independence in Activities of Daily Living; MACS = Manual Ability Classification System; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; mRS = Modified Rankin Scale; SARA = Scale for the Assessment and Rating of Ataxia; VABS = Vineland Adaptive Behaviour Scale; WHO = World Health Organization.

Table 1
Data Utilization Purposes

Table 2
Common Features of Rare Neurogenetic Diseases and Considerations for Data Collection in a Registry Clinical scoring systems such as the GMFCS, GMFC-MLD, or the mRS are easy to collect in registries and provide crude insights on motor problems Wheelchair dependency might be a valuable binary variable to collect For detailed follow-up, more comprehensive assessments of motor function are necessaryFine motor problemsUse of clinical scores can be considered, such as the MACS problems Use of clinical scores can be considered, such as the CFCS or the ELFC-MLD Eating and drinking problems Use of clinical scores can be considered, such as the EDACS Hearing and vision problems Part of several standard questionnaires assessing daily functioning, such as the HUI Cognitive decline Cognitive screening tools: MMSE or MoCA Neuropsychological assessment, including IQ scores , maintaining a central database in the long term is labor-intensive and challenging to sustain.Clear definitions for clinical characteristics do not yet exist for many rare diseases, let alone clear data definitions described in semantic ontologies.Still, there was consensus that registry design should involve both physicians and semantic data/IT experts.AcknowledgmentThe authors are grateful to all participants of the expert focus groups, including Tobias Mentzel as one of the patient advocates, Egbert de Groot as HTA body representative, and all industry representatives including Andrew Olaye and Joost Geenen.The authors also thank the following registries that shared their insightful experiences regarding the practical execution of initiating and managing a registry for a rare neurogenetic disease: 4H registry,Enroll-HD, INPDR, SCA registry, and VWM registry.The authors thank Hans Paalvast, Vera Vroegop, and Klaas Kooistra, all Dutch Healthcare Institute employees, who were involved in the conceptualization of this study and shared their experiences within the program Managing Patient Registries for Expensive Drugs.The following authors of this publication are members of the European Reference Network for Rare Neurological Diseases (ERN-RND; Project ID No. 739510): H. Graessner, T. Bäumer, T. Klockgether, M.S. van der Knaap, and N.I.Wolf, and of the European Reference Network for Hereditary Metabolic Disorders (MetabERN): A.M. Bosch, C.E.M. Hollak, M. Langeveld, and J.M.P. van den Hout.Study Funding The Dutch Healthcare Institute provided funding for the MLD initiative within the context of the program "Managing Patient Registries for Expensive Drugs."DisclosureD.H. Schoenmakers, M. Datema, and N.I.Wolf are members of the MLD initiative, which is an academic registry and collaborative platform for metachromatic leukodystrophy.The MLD initiative was a case study at the program "Managing patient registries for expensive drugs" and received funding from the Dutch Healthcare Institute between April 2021 and March 2023.D.H. Schoenmakers, S. van den Berg, N. Rosenberg, and C.E.M. Hollak are members of platform "Medicijn voor de Maatschappij."This is an academic initiative that aims to support sustainable access to medicines for rare diseases.This platform is financially supported by a grant from "de Nationale Postcode Loterij," a National Lottery that distributes funds raised by this lottery for good causes primarily concerning health and welfare in the Netherlands.L. Adang is consultant and/or coinvestigator for clinical trials in Metachromatic Leukodystrophy and other leukodystrophies (Shire/Takeda, Orchard, Ionis, Lilly).T. Bäumer received funding from the German Research Foundation (DFG, BA 6375/2-1), received speaker and consultant fees from Pelzerhaken Children's Centre, Allergan/Abbvie, Ipsen Pharma and Merz Therapeutics, and received research funding from Allergan/Abbvie, Ipsen Pharma, and Merz Therapeutics.H. Graessner is coordinator of the European Reference Network for Rare Neurological Diseases that receives funding from the European Union.G. Höglinger has ongoing research collaborations with Roche, UCB, and Abbvie, serves as a consultant for Abbvie, Alzprotect, Amylyx, Aprineua, Asceneuron, Bayer, Bial, Biogen, Biohaven, Epidarex, Ferrer, Kyowa Kirin, Lundbeck, Novartis, Retrotope, Roche, Sanofi, Servier, Takeda, Teva, and UCB, received honoraria for scientific presentations from Abbvie, Bayer, Bial, Biogen, Bristol Myers Squibb, Kyowa Kirin, Pfizer, Roche, Teva, UCB, and Zambon, holds a patent on Treatment of Synucleinopathies (US 10,918,628 B2, EP 17 787 904.6-1109/3 525 788), and received publication royalties from Academic Press, Kohlhammer, and Thieme.H. van den Hout received funding for research, clinical trials, and advisory fees from Sanofi, Denali Therapeutics, Amicus Therapeutics, Chiesi,